1. Field of the Invention
This invention relates to a novel process for producing the immunosuppressant agent L-682,993, also described as 31-desmethoxy-31-hydroxy-FK-506, using the new mutant microorganism Streptomyces sp. (MA 7017) ATCC No. 55334, being a blocked second generation mutant of Streptomyces sp. MA 6858. The process involves culturing the new microorganism under aerobic fermentation conditions in an aqueous carbohydrate medium containing a nitrogen nutrient.
2. Brief Description of Disclosures in the Art
In 1983, the US FDA approved Cyclosporin A, an extremely effective anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage, and ulcers which in many cases can be severe.
EPO Publication No. 0184162 to Fujisawa, hereby incorporated by reference, describes a new macrolide immunosuppressant FK-506 (FR-900506) which is reputed to be 100 times more effective than cyclosporin A. The macrolide is produced by fermentation of a particular strain of Streptomyces tsukubaensis. Also described is the closely related macrolide immunosupressant FK-520 (FR-900520), produced by S. hygroscopicus subsp. yakushimaensis.
EPO 0 349 049 (assigned to Merck & Co., Inc.) published Jan. 3, 1990, now U.S. Pat. No. 4,981,792, describes a biotransformation process for producing C-31 desmethyl FK-506, utilizing the microorganism ATCC No. 53711 in the presence of L-679,934 (FK-506) to effect a biotransformation of L-679,934. However a direct fermentation process for producing C-31 desmethyl FK-506 is not described.
EPO 0 388 152 (assigned to Merck & Co., Inc.) published Sep. 19, 1990, describes a new process for the direct fermentation production of C-31 demethylated FK-520 (FR-900520) utilizing the microorganism ATCC No. 53855. However the process is not applicable for the fermentation of C-31 demethylated FK-506.
PCT WO 89/05304 to Fisons, published Jun. 15, 1989, also discloses C-31 desmethyl FK-506, but does not describe or suggest a method of preparation.
Processes for producing C-31 desmethyl FK-506 directly by fermentation of a microorganism, rather than a biotransformation requiring FK-506 as a substrate, are highly desired in the field.